Herpes simplex virus-1 (HSV-1) has many attractive features for further development as an oncolytic and gene transfer vector for prostate cancer therapy. Although many advances have been made in this field in the past decade, we now describe methods to increase the efficacy of treatment using relevant transgenic prostate cancer models mimicking human metastatic prostate cancer. We hypothesize that appropriately chosen chemotherapeutic agents combined with oncolytic HSV vectors will improve anti-tumor efficacy, including after systemic delivery, and that this combination will permit the use of lower, less toxic doses of chemotherapy. We will explore the mechanisms of targeting and anti-tumor efficacy of oncolytic HSV following intravenous delivery. We will study the immune mechanisms of HSV vectors expressing cytokines that can act synergistically to elicit immune destruction of prostate cancer. We hypothesize that oncolytic HSV vectors exert some of their anti-tumor effects by inhibiting angiogenesis within the tumor and that the expression of appropriately chosen cytokines will enhance this anti-angiogenic effect. We will explore these mechanisms of action following both intra-neoplastic and intravenous administration.